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"Long, Li"
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Inflammation balance in skeletal muscle damage and repair
Responding to tissue injury, skeletal muscles undergo the tissue destruction and reconstruction accompanied with inflammation. The immune system recognizes the molecules released from or exposed on the damaged tissue. In the local minor tissue damage, tissue-resident macrophages sequester pro-inflammatory debris to prevent initiation of inflammation. In most cases of the skeletal muscle injury, however, a cascade of inflammation will be initiated through activation of local macrophages and mast cells and recruitment of immune cells from blood circulation to the injured site by recongnization of damage-associated molecular patterns (DAMPs) and activated complement system. During the inflammation, macrophages and neutrophils scavenge the tissue debris to release inflammatory cytokines and the latter stimulates myoblast fusion and vascularization to promote injured muscle repair. On the other hand, an abundance of released inflammatory cytokines and chemokines causes the profound hyper-inflammation and mobilization of immune cells to trigger a vicious cycle and lead to the cytokine storm. The cytokine storm results in the elevation of cytolytic and cytotoxic molecules and reactive oxygen species (ROS) in the damaged muscle to aggravates the tissue injury, including the healthy bystander tissue. Severe inflammation in the skeletal muscle can lead to rhabdomyolysis and cause sepsis-like systemic inflammation response syndrome (SIRS) and remote organ damage. Therefore, understanding more details on the involvement of inflammatory factors and immune cells in the skeletal muscle damage and repair can provide the new precise therapeutic strategies, including attenuation of the muscle damage and promotion of the muscle repair.
Journal Article
LightGBM integration with modified data balancing and whale optimization algorithm for rock mass classification
The accurate prediction of uneven rock mass classes is crucial for intelligent operation in tunnel-boring machine (TBM) tunneling. However, the classification of rock masses presents significant challenges due to the variability and complexity of geological conditions. To address these challenges, this study introduces an innovative predictive model combining the improved EWOA (IEWOA) and the light gradient boosting machine (LightGBM). The proposed IEWOA algorithm incorporates a novel parameter
l
for more effective position updates during the exploration stage and utilizes sine functions during the exploitation stage to optimize the search process. Additionally, the model integrates a minority class technique enhanced with a random walk strategy (MCT-RW) to extend the boundaries of minority classes, such as Classes II, IV, and V. This approach significantly improves the recall and F
1
-score for these rock mass classes. The proposed methodology was rigorously evaluated against other predictive algorithms, demonstrating superior performance with an accuracy of 94.74%. This innovative model not only enhances the accuracy of rock mass classification but also contributes significantly to the intelligent and efficient construction of TBM tunnels, providing a robust solution to one of the key challenges in underground engineering.
Journal Article
MiR‐205 promotes endothelial progenitor cell angiogenesis and deep vein thrombosis recanalization and resolution by targeting PTEN to regulate Akt/autophagy pathway and MMP2 expression
MicroRNAs (MiRNAs, MiRs) represent a class of conserved small non‐coding RNAs that affect post‐transcriptional gene regulation and play a vital role in angiogenesis, proliferation, apoptosis, migration and invasion. They are essential for a wide range of physiological and pathological processes, especially for vascular diseases. However, data concerning miRNAs in endothelial progenitor cells (EPCs) and deep vein thrombosis (DVT) remain incomplete. We explored miRNAs that modulate angiogenesis in EPCs and thrombolysis, and analysed their underlying mechanisms using a DVT model, dual‐luciferase reporter assay, qRT‐PCR, Western blot, immunofluorescence staining, flow cytometry analysis, CCK‐8 assay, angiogenesis assay, wound healing and Transwell assay. We found that miR‐205 enhanced the homing ability of EPCs to DVT sites and promoted thrombosis resolution and recanalization, which significantly reduced venous thrombus. Additionally, we demonstrated that miR‐205 overexpression significantly enhanced angiogenesis in vivo and in vitro, migration, invasion, F‐actin filaments and proliferation in EPCs, and inhibited cell apoptosis. Conversely, down‐regulation of miR‐205 played the opposite role in EPCs. Importantly, this study demonstrated that miR‐205 directly targeted PTEN to modulate the Akt/autophagy pathway and MMP2 expression, subsequently playing a key role in EPC function and DVT recanalization and resolution. These results elucidated the pro‐angiogenesis effects of miR‐205 in EPCs and established it as a potential target for DVT treatment.
Journal Article
Exosomal miR-21 promotes proliferation, invasion and therapy resistance of colon adenocarcinoma cells through its target PDCD4
Exosomes contain cell-specific collections of bioactive materials including proteins, lipids, and RNAs that are transported to recipient cells to exert their impacts. MicroRNAs (miRNAs) can function as tumor suppressor or oncogenic genes and miR-21 is one of the most frequently up-regulated miRNAs in solid tumors including colon cancer. The aim of this study was to investigate the role of miR-21, secreted from exosomes, in proliferation and invasion of colon cancer, along with the mechanistic details. We used a variety of biochemical techniques including ultracentrifugation-based exosome purification, electron transmission microscopy, western blot and RT-qPCR to detect the expression levels of miR-21 in exosomes purified from culture media of human colonic adenocarcinoma cell lines. We then performed functional and mechanistic studies using three colon cancer cell lines HT29, T84 and LS174 as well as the normal colon epithelial cells CRL1831. miR-21 target PDCD4 was investigated for its role in mediating miR-21 effects. Expression of miR-21 was significantly up-regulated in exosomes of colon cancer cells, compared to the normal human colon epithelial cells. Treatment of colon cancer cells with isolated exosomes or miR-21 led to an increased expression of genes involved in cell proliferation, invasion and extracellular matrix formation. miR-21 targets PDCD4, TPM1 and PTEN were down-regulated by exosomes and silencing of PDCD4 mimicked miR-21 functional effects, even the induced resistance against 5-FU. Our study suggests that targeted inhibition of exosomes, particularly those carrying miR-21, may represent a novel approach for treatment of colorectal cancer.
Journal Article
Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder. The mechanisms underlying ASD are unclear. Astrocyte alterations are noted in ASD patients and animal models. However, whether astrocyte dysfunction is causal or consequential to ASD-like phenotypes in mice is unresolved. Type 2 inositol 1,4,5-trisphosphate 6 receptors (IP3R2)-mediated Ca
2+
release from intracellular Ca
2+
stores results in the activation of astrocytes. Mutations of the IP3R2 gene are associated with ASD. Here, we show that both IP3R2-null mutant mice and astrocyte-specific IP3R2 conditional knockout mice display ASD-like behaviors, such as atypical social interaction and repetitive behavior. Furthermore, we show that astrocyte-derived ATP modulates ASD-like behavior through the P2X2 receptors in the prefrontal cortex and possibly through GABAergic synaptic transmission. These findings identify astrocyte-derived ATP as a potential molecular player in the pathophysiology of ASD.
Astrocytes contribute to autism spectrum disorder (ASD) pathophysiology. Here, the authors show that IP3R2 conditional KO mice show ASD-like behaviours and identify astrocyte-derived ATP as a modulator of these behaviours in mice.
Journal Article
Study on the mechanical properties of TPMS porous structure
In this study, the porous structure of TPMS is designed and prepared by additive manufacturing technology (AM). The deformation behaviors of these structures are investigated. The results demonstrate that the Gyroid structure exhibits excellent mechanical properties with a strength limit of 372 MPa. The layer-by-layer damage is the process of destruction demonstrated by the Gyroid porous structure. At 30% strain, a diagonal shear band appears, and the angle of the shear band is 45° from the compression direction. Diamond and Primitive porous structures initially exhibit damage at the junction of the unit cell, with a shear band appearing at 20% strain.
Journal Article
Immune infiltration in renal cell carcinoma
Immune infiltration of tumors is closely associated with clinical outcome in renal cell carcinoma (RCC). Tumor‐infiltrating immune cells (TIICs) regulate cancer progression and are appealing therapeutic targets. The purpose of this study was to determine the composition of TIICs in RCC and further reveal the independent prognostic values of TIICs. CIBERSORT, an established algorithm, was applied to estimate the proportions of 22 immune cell types based on gene expression profiles of 891 tumors. Cox regression was used to evaluate the association of TIICs and immune checkpoint modulators with overall survival (OS). We found that CD8+ T cells were associated with prolonged OS (hazard ratio [HR] = 0.09, 95% confidence interval [CI].01‐.53; P = 0.03) in chromophobe carcinoma (KICH). A higher proportion of regulatory T cells was associated with a worse outcome (HR = 1.59, 95% CI 1.23‐.06; P < 0.01) in renal clear cell carcinoma (KIRC). In renal papillary cell carcinoma (KIRP), M1 macrophages were associated with a favorable outcome (HR = .43, 95% CI .25‐.72; P < 0.01), while M2 macrophages indicated a worse outcome (HR = 2.55, 95% CI 1.45‐4.47; P < 0.01). Moreover, the immunomodulator molecules CTLA4 and LAG3 were associated with a poor prognosis in KIRC, and IDO1 and PD‐L2 were associated with a poor prognosis in KIRP. This study indicates TIICs are important determinants of prognosis in RCC meanwhile reveals potential targets and biomarkers for immunotherapy development. We described the immune landscape in detail, revealing the distinct immune infiltration patterns of different subtypes and stages of RCC. We further revealed relationships between TIIC and molecular subtypes, tumor stages, recurrent genomic alterations and survival in RCC. Our work advances the understanding of immune response meanwhile reveals potential targets and biomarkers for immunotherapy development.
Journal Article
Epidemiologic relationship between periodontitis and type 2 diabetes mellitus
Background
To systematically review the epidemiologic relationship between periodontitis and type 2 diabetes mellitus (T2DM).
Methods
Four electronic databases were searched up until December 2018. The manual search included the reference lists of the included studies and relevant journals. Observational studies evaluating the relationship between T2DM and periodontitis were included
.
Meta-analyses were conducted using STATA.
Results
A total of 53 observational studies were included. The Adjusted T2DM prevalence was significantly higher in periodontitis patients (OR = 4.04,
p
= 0.000), and vice versa (OR = 1.58, p = 0.000). T2DM patients had significantly worse periodontal status, as reflected in a 0.61 mm deeper periodontal pocket, a 0.89 mm higher attachment loss and approximately 2 more lost teeth (all
p
= 0.000), than those without T2DM. The results of the cohort studies found that T2DM could elevate the risk of developing periodontitis by 34% (
p
= 0.002). The glycemic control of T2DM patients might result in different periodontitis outcomes. Severe periodontitis increased the incidence of T2DM by 53% (
p
= 0.000), and this result was stable. In contrast, the impact of mild periodontitis on T2DM incidence (RR = 1.28,
p
= 0.007) was less robust.
Conclusions
There is an evident bidirectional relationship between T2DM and periodontitis. Further well-designed cohort studies are needed to confirm this finding. Our results suggest that both dentists and physicians need to be aware of the strong connection between periodontitis and T2DM. Controlling these two diseases might help prevent each other’s incidence.
Journal Article
saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription
Small activating RNAs （saRNAs） targeting specific promoter regions are able to stimulate gene expression at the transcriptional level, a phenomenon known as RNA activation （RNAa）. It is known that RNAa depends on Ago2 and is associated with epigenetic changes at the target promoters. However, the precise molecular mechanism of RNAa remains elusive. Using human CDKN1A （p21） as a model gene, we characterized the molecular nature of RNAa. We show that saRNAs guide Ago2 to and associate with target promoters, saRNA-loaded Ago2 facilitates the assembly of an RNA-induced transcriptional activation （RITA） complex, which, in addition to saRNA-Ago2 complex, includes RHA and CTR9, the latter being a component of the PAFI complex. RITA interacts with RNA polymerase II to stimulate transcription initiation and productive elongation, accompanied by monoubiquitination of histone 2B. Our results establish the existence of a cellular RNA-guided genome-targeting and transcriptional activation mechanism and provide important new mechanistic insights into the RNAa process.
Journal Article